Abstract Sentia seeks to bring to fruition 40 years (1975 - 2015) of NIDDK-funded (P01 DK026741 PIs: W. Vale, C. Rivier, J. Spiess and J. Rivier) academic research to achieve translational drug candidacy by blocking both corticotropin-releasing factor (CRF) receptors CRF1/2 with potent astressin peptide antagonists. Present assets of Sentia include world-wide, patent-protected, first-in-class peptide drug candidates and intellectual property that targets, among others, the regulation of the stress response system. Scientific evidence documents that potentially dozens of current human ailments can benefit from the use of stress-neutralizing compounds to achieve temporal or permanent homeostasis. In particular, irritable bowel syndrome (IBS) is well established to be a stress-sensitive condition with visceral pain being the hallmark. Alleviating visceral pain in IBS patients is still an unmet need and the market for managing and/or curing the symptoms is conservatively estimated to be in the $10B range. Astressin therapeutics would represent a first-in-class opportunity to safely and effectively treat IBS patients with injectable peptide analogs that could represent a paradigm shift in therapeutic intervention away from conventional short-acting oral small molecules providing patients a different option for long-acting relief. Therefore, the objective of the Phase I application is to obtain relevant quantities of astressin CRF1/2 antagonists (compounds 1-3) manufactured following the Fmoc strategy, that is likely the approach to be taken commercially by CROs, and provide preclinical evidence of their safety, efficacy and long-lasting effects to reduce stress-related visceral hyperalgesia. In aim 1, a potential clinical candidate for development will be selected from the acetate salts of compounds 1-3, i.e., astressin C, [C?MeVal19,32]- astressin C and hexanoyl-astressin D, originally synthesized and tested using the Boc strategy. Their MW is around 3,900 daltons, well within the desirable range for chemical total synthesis, biological characterization and fibrils formation for long duration of action.1 It is expected that the acetate salts of these analogs will share the favorable physiochemical properties of the corresponding tri-fluoro acetate. Substantially, there are no obvious properties that would disqualify a selected candidate. In Aim 2, these CRF receptor antagonists will be tested preclinically for their ability to modulate visceral hypersensitivity in an experimental stress-related model of IBS developed by the subcontracted academic institution, the UCLA Center for Digestive Diseases Research. If validated, results from these preclinical experiments will allow Sentia to select a first candidate and back up compound(s).